dbSNP rs8192587: NOTCH4:c.799+42G>C (chr6-32220936-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_004557.4(NOTCH4):c.799+42G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,595,952 control chromosomes in the GnomAD database, including 548 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.020 ( 46 hom., cov: 33)

Exomes 𝑓: 0.024 ( 502 hom. )

Consequence

NOTCH4
NM_004557.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.450

Publications

6 publications found

Variant links:

Genes affected

NOTCH4 (HGNC:7884): (notch receptor 4) This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor may play a role in vascular, renal and hepatic development. Mutations in this gene may be associated with schizophrenia. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

NOTCH4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0197 (3004/152304) while in subpopulation SAS AF = 0.0313 (151/4828). AF 95% confidence interval is 0.0272. There are 46 homozygotes in GnomAd4. There are 1531 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 3004 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4 link	c.799+42G>C	intron_variant	Intron 4 of 29	ENST00000375023.3	NP_004548.3	Q99466-1A0A1U9X983
NOTCH4	NR_134949.2 link	n.938+42G>C	intron_variant	Intron 4 of 29
NOTCH4	NR_134950.2 link	n.938+42G>C	intron_variant	Intron 4 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3 link	c.799+42G>C		intron_variant	Intron 4 of 29	1	NM_004557.4	ENSP00000364163.3		Q99466-1
NOTCH4	ENST00000473562.1 link	n.928+42G>C		intron_variant	Intron 4 of 10	1

Frequencies

GnomAD3 genomes

AF:

0.0198

AC:

3006

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00369

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.0213

Gnomad ASJ

AF:

0.0357

Gnomad EAS

AF:

0.00406

Gnomad SAS

AF:

0.0315

Gnomad FIN

AF:

0.0357

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0262

Gnomad OTH

AF:

0.0296

GnomAD2 exomes

AF:

0.0251

AC:

5931

AN:

236178

AF XY:

0.0270

show subpopulations

Gnomad AFR exome

AF:

0.00319

Gnomad AMR exome

AF:

0.0151

Gnomad ASJ exome

AF:

0.0404

Gnomad EAS exome

AF:

0.00482

Gnomad FIN exome

AF:

0.0379

Gnomad NFE exome

AF:

0.0287

Gnomad OTH exome

AF:

0.0252

GnomAD4 exome

AF:

0.0240

AC:

34638

AN:

1443648

Hom.:

502

Cov.:

AF XY:

0.0247

AC XY:

17668

AN XY:

716024

show subpopulations

African (AFR)

AF:

0.00320

AC:

106

AN:

33098

American (AMR)

AF:

0.0155

AC:

669

AN:

43254

Ashkenazi Jewish (ASJ)

AF:

0.0364

AC:

893

AN:

24502

East Asian (EAS)

AF:

0.00570

AC:

225

AN:

39492

South Asian (SAS)

AF:

0.0339

AC:

2840

AN:

83848

European-Finnish (FIN)

AF:

0.0380

AC:

2002

AN:

52710

Middle Eastern (MID)

AF:

0.0122

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.0240

AC:

26401

AN:

1101662

Other (OTH)

AF:

0.0241

AC:

1433

AN:

59426

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

2362

4724

7085

9447

11809

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

942

1884

2826

3768

4710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0197

AC:

3004

AN:

152304

Hom.:

Cov.:

AF XY:

0.0206

AC XY:

1531

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00368

AC:

153

AN:

41564

American (AMR)

AF:

0.0212

AC:

325

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0357

AC:

124

AN:

3470

East Asian (EAS)

AF:

0.00407

AC:

AN:

5160

South Asian (SAS)

AF:

0.0313

AC:

151

AN:

4828

European-Finnish (FIN)

AF:

0.0357

AC:

379

AN:

10626

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0262

AC:

1782

AN:

68026

Other (OTH)

AF:

0.0293

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

165

331

496

662

827

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0239

Hom.:

Bravo

AF:

0.0176

Asia WGS

AF:

0.00953

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

8.6

(source)

DANN

Benign

0.59

PhyloP100

0.45

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over